Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Sabater‐Lleal, Maria; Huffman, Jennifer E.; Vries, Paul S. de; Marten, Jonathan; Mastrangelo, Michael A.; Song, Ci; Pankratz, Nathan; Ward‐Caviness, Cavin; Yanek, Lisa R.; Trompet, Stella; Delgado, Graciela; Guo, Xiuqing; Bartz, Traci M.; Martinez-Perez, Ángel; Germain, Marine; Haan, Hugoline G. de; Ozel, Ayse Bilge; Polašek, Ozren; Smith, Albert V.; Eicher, John D.; Reiner, Alex P.; Tang, Weihong; Davies, Neil M; Stott, David J.; Rotter, Jerome I.; Tofler, Geoffrey H.; Boerwinkle, Eric; Maat, Moniek P.M. de; Kleber, Marcus E.; Welsh, Paul; Brody, Jennifer A.; Chen, Ming-Huei; Vaidya, Dhananjay; Soria, José Manuel Nieto; Suchon, Pierre; Vlieg, Astrid van Hylckama; Desch, Karl C.; Kolčić, Ivana; Joshi, Peter K.; Launer, Lenore J.; Harris, Tamara B.; Campbell, Harry; Rudan, Igor; Becker, Diane M.; Li, Jun Z.; Rivadeneira, Fernando; Uitterlinden, André G.; Hofman, Albert; Franco, Oscar H.; Cushman, Mary; Psaty, Bruce M.; Morange, Pierre‐Emmanuel; McKnight, Barbara; Chong, Michael; Fernández‐Cadenas, Israel; Rosand, Jonathan; Lindgren, Arne; Gudnason, Vilmundur; Wilson, James F.; Hayward, Caroline; Ginsburg, David; Fornage, Myriam; Rosendaal, Frits R.; Souto, Juan Carlos; Becker, Lewis C.; Jenny, Nancy S.; März, Winfried; Jukema, J. Wouter; Dehghan, Abbas; Trégouët, David‐Alexandre; Morrison, Alanna C.; Johnson, Andrew D.; O’Donnell, Christopher J; Strachan, David P.; Lowenstein, Charles J.; Smith, Nicholas L.

doi:10.1161/circulationaha.118.034532

Cited by 115 publications

(147 citation statements)

References 40 publications

(39 reference statements)

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“…These identified genes need further functional characterization to fully characterize their role in VWF regulation. 81 This may contribute to the progress and understanding of pathogenesis of the "low VWF" phenotype and provide new insights into the molecular diagnosis of type 1 VWD. 73 Recent studies have investigated the role of glycosylation and sialylation of VWF in the regulation of VWF functional activity, proteolysis, and clearance.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…Several of these candidate genes that showed a clear change in VWF levels upon silencing have been shown to participate in vesicle trafficking and exocytosis, intracellular signaling, and inflammatory response. 81 The majority of these novel loci seem to affect the regulation of VWF secretion from endothelial cells and/or megakaryocytes. Nevertheless, these associations need further confirmation and validation.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…Continued)might increase vascular permeability in acute inflammation C2CD4B silencing resulted in a strong upregulation of VWF release in basal and stimulus conditions DDAVP, desmopressin; FVIII, factor VIII; SNV, single-nucleotide variant; VNTR, variable number tandem repeat; WPB, Weibel-Palade bodies; VWD, von Willebrands disease; VWF, von Willebrand factor. Source: summarized from Sabater-Lleal et al81 and Swystun and Lilicrap 73. …”

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confidence: 99%

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Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Žolková

Sokol

Šimurda

et al. 2019

Semin Thromb Hemost

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Sequencing of the gene encoding for von Willebrand factor (VWF) has brought new insight into the physiology of VWF as well as its pathophysiology in the context of von Willebrand disease (VWD). Molecular testing in VWD patients has shown high variability in the overall genetic background of this condition. Almost 600 mutations and many disease-causing mechanisms have been described in the 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to types 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next-generation sequencing methods that are more cost- and time-effective. Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (type 1), appear to be free of mutations in VWF. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO possibly affecting VWF levels, and such findings will need further validation studies.

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Section: Future Perspectivesmentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Žolková

Sokol

Šimurda

et al. 2019

Semin Thromb Hemost

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“…An updated GWAS meta‐analysis from the CHARGE consortium, recently described in abstract form, included results from a discovery cohort of > 46 000 normal individuals of European, African, East Asian and Hispanic descent . Eleven additional QTL were found to be associated with plasma VWF levels: ARSA , C2CD4B , DAB2IP , FCHO2 , GIMAP7 , HLA‐DGA1 , OR13C5 , PDHB , RAB5C , ST3GAL4 , and TAB1 / SYNGR1 .…”

Section: Identification Of Non‐vwf Loci That Influence Vwf Levelsmentioning

confidence: 99%

Genetic regulation of plasma von Willebrand factor levels in health and disease

Swystun

Lillicrap

2018

Journal of Thrombosis and Haemostasis

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To cite this article: Swystun LL, Lillicrap D. Genetic regulation of plasma von Willebrand factor levels in health and disease. J Thromb Haemost 2018; 16: 2375-90. of genetic modifiers of plasma VWF levels may allow for better molecular diagnosis of type 1 VWD, and enable the identification of individuals at increased risk for thrombosis. Validation of trait-mapping studies with in vitro and in vivo methodologies has led to novel insights into the life cycle of VWF and the pathogenesis of quantitative VWF abnormalities.

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“…2C). We neither detected associations with plasma levels of other measured proteins in the coagulation cascade and protein C pathway, including protein S (the cofactor of APC), nor with risk factors for thrombosis, including fibrinogen, von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and the thrombolytic agent tissue plasminogen activator (tPA) (P>0.05) [32][33][34][35] (Fig. 2C).…”

Section: Association Of Procr-ps219g With Cardiovascular Diseases Anmentioning

confidence: 96%

Elucidating mechanisms of genetic cross-disease associations: an integrative approach implicates protein C as a causal pathway in arterial and venous diseases

Stacey

Chen

Howson

et al. 2020

Preprint

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Genome-wide association studies have identified many individual genetic loci associated with multiple complex traits and common diseases. There are, however, few examples where the molecular basis of such pleiotropy has been elucidated. To address this challenge, we describe an integrative approach, focusing on the p.Ser219Gly (rs867186 A>G) variant in the PROCR gene (encoding the endothelial protein C receptor, EPCR), which has been associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. In a phenome scan of 12 cardiometabolic diseases and 24 molecular factors, we found that PROCR-219Gly associated with higher plasma levels of zymogenic and activated protein C as well as coagulation factor VII. Using statistical colocalization and Mendelian randomization analyses, we uncovered shared genetic etiology across activated protein C, factor VII, CAD and VTE, identifying p.S219G as the likely causal variant at the locus. In a recall-by-genotype study of 52 healthy volunteers stratified by p.S219G, we detected 2.5-fold higher soluble EPCR levels and 1.2-fold higher protein C levels in plasma per effect allele, suggesting the allele induces EPCR shedding from the membrane of endothelial cells. Finally, in cell adhesion assays, we found that increasing concentrations of activated protein C, but not soluble EPCR, reduced leukocyte-endothelial cell adhesion, a marker for vascular inflammation. These results support a role for protein C as a causal factor in arterial and venous diseases, suggesting that PROCR-219Gly protects against CAD through anti-inflammatory mechanisms while it promotes VTE risk through pro-thrombotic mechanisms. Overall, our study illustrates a multi-modal approach that can help reveal molecular underpinnings of cross-disease associations.

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Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Cited by 115 publications

References 40 publications

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Genetic regulation of plasma von Willebrand factor levels in health and disease

Elucidating mechanisms of genetic cross-disease associations: an integrative approach implicates protein C as a causal pathway in arterial and venous diseases

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